A number of antibodies have been developed, including for their use in therapies for a variety of diseases, disorders or conditions. For example, in the fall of 1997, the anti-CD20 monoclonal antibody, rituximab (currently sold under the brand name RITUXAN®), was approved for the treatment of refractory or relapsed low-grade B-cell non-Hodgkin's lymphoma (NHL). Rituximab has since become a mainstay of treatment for low-grade NHL and over 400,000 patients worldwide have been treated with rituximab. Despite this extensive clinical experience, the mechanism of action of rituximab remains unclear, as does the nature of resistance.
Rituximab is a chimeric antibody consisting of a murine CD20-binding variable region linked to human IgG1 constant region. CD20 is a cell surface protein expressed on B-lymphocytes. CD20 has four transmembrane domains and has been proposed to act as an ion channel; however, the function of CD20 remains poorly understood. Phase II trials of rituximab in people with refractory or relapsed low grade or follicular NHL demonstrated a 50% response rate. While the nature of de novo resistance to rituximab is unclear, such resistance is very rarely due to loss of the CD20 antigen, which cannot be shed or internalized and is rarely down-regulated. Despite these properties of CD20, acquired resistance to rituximab is common in that only half of patients previously responding to rituximab will respond to a second course of treatment.
An effective and practical diagnostic protocol which could provide information as to whether a patient is or is not responsive to a therapy, including an antibody therapy such as rituximab therapy, would be desirable for a number of reasons, including avoidance of delays in alternative treatments, elimination of exposure to adverse effects of the therapy and reduction of unnecessary expense. As such, there is interest in the development of protocols that can accurately predict whether or not a patient is responsive to such therapies. There is also an interest in the development of antibodies and antibody therapies that would be effective or more effective in patients that were non-responsive or poorly responsive to a particular therapy.